Caenorhabditis elegans
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ABSTRACT:
PROVIDER: PRJNA223323 | ENA |
REPOSITORIES: ENA
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Project description:The Wnt signaling pathway plays a fundamental role during the development of metazoans, where it functions in the regulation of diverse processes including cell fate specification, cell migration, and stem cell renewal. Activation of the beta-catenin dependent or canonical Wnt signaling pathway upregulates expression of Wnt target genes to mediate an appropriate cellular response. In the nematode C. elegans, a Wnt signaling pathway similar to the canonical pathway regulates several processes during larval development, however few target genes of this pathway have been identified. To address this deficit, we conditionally activated Wnt signaling in living animals during a defined stage of larval life by expressing a dominant, activated beta-catenin protein, then used microarray analysis to identify genes showing altered expression compared to control animals. In this way we identified 166 differentially expressed genes, of which 104 were upregulated. A subset of the upregulated genes were validated by qPCR and showed altered expression in Wnt pathway mutants with decreased or increased Wnt signaling; we consider these genes to be candidate Wnt pathway targets in the C. elegans hermaphrodite larva. Amongst these was a group of 6 genes, including the cuticular collagen genes, bli-1 col-38, col-49 and col-71, that show a peak of expression in the mid L4 stage during normal development. The L4 expression of these genes suggests they may be expressed for use in the adult cuticle, and consistent with this, reduction of function for several of the genes leads to phenotypes suggestive of defects in cuticle function or integrity. Therefore this work has identified a large number of putative Wnt pathway target genes during larval life, including a small subset of Wnt-regulated collagen genes that may function in synthesis of the adult cuticle. a single pulse heat shock, inducing over-activated signal transduction in the Exp. Three treatment with three control strains of the identical genetical background strains
2014-05-13 | E-GEOD-51502 | biostudies-arrayexpress
Project description:The Wnt signaling pathway plays a fundamental role during the development of metazoans, where it functions in the regulation of diverse processes including cell fate specification, cell migration, and stem cell renewal. Activation of the beta-catenin dependent or canonical Wnt signaling pathway upregulates expression of Wnt target genes to mediate an appropriate cellular response. In the nematode C. elegans, a Wnt signaling pathway similar to the canonical pathway regulates several processes during larval development, however few target genes of this pathway have been identified. To address this deficit, we conditionally activated Wnt signaling in living animals during a defined stage of larval life by expressing a dominant, activated beta-catenin protein, then used microarray analysis to identify genes showing altered expression compared to control animals. In this way we identified 166 differentially expressed genes, of which 104 were upregulated. A subset of the upregulated genes were validated by qPCR and showed altered expression in Wnt pathway mutants with decreased or increased Wnt signaling; we consider these genes to be candidate Wnt pathway targets in the C. elegans hermaphrodite larva. Amongst these was a group of 6 genes, including the cuticular collagen genes, bli-1 col-38, col-49 and col-71, that show a peak of expression in the mid L4 stage during normal development. The L4 expression of these genes suggests they may be expressed for use in the adult cuticle, and consistent with this, reduction of function for several of the genes leads to phenotypes suggestive of defects in cuticle function or integrity. Therefore this work has identified a large number of putative Wnt pathway target genes during larval life, including a small subset of Wnt-regulated collagen genes that may function in synthesis of the adult cuticle.
2014-05-13 | GSE51502 | GEO
Project description:Up to 41% of hepatocellular carcinomas (HCCs) result from activating mutations in the CTNNB1 gene encoding β-catenin. β-catenin has dual cellular functions as a component of the Wnt signaling pathway and adherens junctions. HCC-associated CTNNB1 mutations stabilize the β-catenin protein, leading to nuclear and/or cytoplasmic localization of β-catenin and downstream activation of Wnt target genes. In patient HCC samples, β-catenin nuclear and cytoplasmic localization are typically patchy, even among HCC with highly active CTNNB1 mutations. The functional and clinical relevance of this heterogeneity in β-catenin activation are not well understood. To define mechanisms of β-catenin-driven HCC initiation, we generated a Cre-lox system that enabled switching on activated β-catenin in 1) a small number of hepatocytes in early development; or 2) the majority of hepatocytes in later development or adulthood. We discovered that switching on activated β-catenin in a subset of larval hepatocytes was sufficient to drive HCC initiation. To determine the role of Wnt/β-catenin signaling heterogeneity later in hepatocarcinogenesis, we performed RNA-seq analysis of zebrafish β-catenin-driven HCC. Ingenuity Pathway Analysis of differentially expressed genes in the Cre-lox HCC model revealed that “Cancer” and “Liver Tumor” categories were significantly altered, indicating transcriptional similarities with human HCC and other vertebrate HCC models. At the single-cell level, 2.9% to 15.2% of hepatocytes from zebrafish β-catenin-driven HCC expressed two or more of the Wnt target genes axin2, mtor, glula, myca, and wif1, indicating focal activation of Wnt signaling in established tumors. Thus, heterogeneous β-catenin activation drives HCC initiation and persists throughout hepatocarcinogenesis.
2019-09-27 | GSE137787 | GEO
Project description:Up to 41% of hepatocellular carcinomas (HCCs) result from activating mutations in the CTNNB1 gene encoding β-catenin. β-catenin has dual cellular functions as a component of the Wnt signaling pathway and adherens junctions. HCC-associated CTNNB1 mutations stabilize the β-catenin protein, leading to nuclear and/or cytoplasmic localization of β-catenin and downstream activation of Wnt target genes. In patient HCC samples, β-catenin nuclear and cytoplasmic localization are typically patchy, even among HCC with highly active CTNNB1 mutations. The functional and clinical relevance of this heterogeneity in β-catenin activation are not well understood. To define mechanisms of β-catenin-driven HCC initiation, we generated a Cre-lox system that enabled switching on activated β-catenin in 1) a small number of hepatocytes in early development; or 2) the majority of hepatocytes in later development or adulthood. We discovered that switching on activated β-catenin in a subset of larval hepatocytes was sufficient to drive HCC initiation. To determine the role of Wnt/β-catenin signaling heterogeneity later in hepatocarcinogenesis, we performed RNA-seq analysis of zebrafish β-catenin-driven HCC. Ingenuity Pathway Analysis of differentially expressed genes in the Cre-lox HCC model revealed that “Cancer” and “Liver Tumor” categories were significantly altered, indicating transcriptional similarities with human HCC and other vertebrate HCC models. At the single-cell level, 2.9% to 15.2% of hepatocytes from zebrafish β-catenin-driven HCC expressed two or more of the Wnt target genes axin2, mtor, glula, myca, and wif1, indicating focal activation of Wnt signaling in established tumors. Thus, heterogeneous β-catenin activation drives HCC initiation and persists throughout hepatocarcinogenesis.
2019-09-27 | GSE137784 | GEO
Project description:The Wnt/β-catenin signaling pathway is a critical regulator of development and stem cell maintenance. Mounting evidence suggests that the context-specific outcome of Wnt signaling is determined by the collaborative action of multiple transcription factors, including members of the highly conserved forkhead box (FOX) protein family. The contribution of FOX transcription factors to Wnt signaling has not been investigated in a systemic manner. Here, by combining β-catenin reporter assays with Wnt pathway-focused qPCR arrays and proximity proteomics of selected FOX family members, we determine that most FOX proteins are involved in the regulation of Wnt pathway activity and the expression of Wnt ligands and target genes. We conclude that FOX proteins are common regulators of the Wnt/β-catenin pathway that may control the outcome of Wnt signaling in a tissue-specific manner.
2023-04-19 | PXD038811 | Pride
Project description:Tumor: tumor microenvironment (TME) interactions are critical for tumor progression and the composition and structure of the local extracellular matrix (ECM) are key determinants of tumor metastasis. We recently reported that activation of Wnt/beta- catenin signaling in Ewing sarcoma cells induces widespread transcriptional changes that are associated with acquisition of a metastatic tumor phenotype. Significantly, ECM protein-encoding genes were found to be enriched among Wnt/beta-catenin induced transcripts, leading us to hypothesize that activation of canonical Wnt signaling might induce changes in the Ewing sarcoma secretome. To address this hypothesis, conditioned media from Ewing sarcoma cell lines cultured in the presence or absence of Wnt3a was collected for proteomic analysis. Label-free mass spectrometry was used to identify and quantify differentially secreted proteins. We then used in silico databases to identify only proteins annotated as secreted. Comparison of the secretomes of two Ewing sarcoma cell lines revealed numerous shared proteins, as well as a degree of heterogeneity, in both basal and Wnt-stimulated conditions. Gene set enrichment analysis of secreted proteins revealed that Wnt stimulation reproducibly resulted in increased secretion of proteins involved in ECM organization, ECM receptor interactions, and collagen formation. In particular, Wnt-stimulated Ewing sarcoma cells upregulated secretion of structural collagens, as well as matricellular proteins, such as the metastasis-associated protein, tenascin C (TNC). Interrogation of published databases confirmed reproducible correlations between Wnt/beta-catenin activation and TNC and COL1A1 expression in patient tumors. In summary, this first study of the Ewing sarcoma secretome reveals that Wnt/beta-catenin activated tumor cells upregulate secretion of ECM proteins. Such Wnt/beta-catenin mediated changes are likely to impact on tumor: TME interactions that contribute to metastatic progression.
2018-02-07 | PXD007909 | Pride
Project description:Canonical Wnt/β-catenin signalling is an essential regulator of various cellular functions throughout development and adulthood. Aberrant Wnt/β-catenin signalling also contributes to various pathologies including cancer, necessitating an understanding of cell context dependent mechanisms regulating this pathway. Since protein-protein interactions underpin β-catenin function and localization, we sought to identify novel β-catenin interacting partners by affinity purification coupled with tandem mass spectrometry in vascular smooth muscle cells (VSMCs), where β-catenin is involved in both physiological and pathological control of cell proliferation. Here, we report novel components of the VSMC β-catenin interactome.
2018-10-25 | PXD010421 | Pride
Project description:This study aimed to further understand context-specific direct Wnt target gene expression through the use of beta-catenin and FoxH1 ChIP Sequencing data at various developmental stages representing both maternal and zygotic Wnt signalling. Results were further supported through the use of RNA sequencing data from beta-catenin, FoxH1 and nodal gene knock down assays.
2020-06-21 | E-MTAB-8555 | biostudies-arrayexpress
Project description:Wnt/β-catenin signaling is a highly organized biochemical cascade that triggers a gene expression program in the signal-receiving cell. The Wnt/β-catenin-driven transcriptional response is involved in virtually all cellular processes during development, homeostasis, and its deregulation causes human disease. However, outstanding questions remain unanswered. A first question concerns cell-specificity: how this response is integrated into lineage-specific choices is still unknown. A second question concerns time: it is not known whether β-catenin associates with its targets simultaneously or in a time-dependent fashion. For instance, while TCF/LEF and other components of the Wnt transcriptional complex are constitutively associated with the chromatin, it is β-catenin arrival, upon Wnt induction, that launches target genes transcription. Therefore, discovering the dynamics of the genome-wide β-catenin binding pattern is required to unambiguously define the direct targets of Wnt signaling To address these questions, we realized a time-resolved atlas of β-catenin genome-wide occupancy in two human cell types, human embryonic kidney cells 293T (HEK293T) and human embryonic stem cells (hESCs). To this end, we treated HEK293T and hESCs with the GSK3 inhibitor/Wnt activator CHIR99021 (10 mM) for 3 days, and assessed β-catenin binding via CUT&RUN-LoV-U (Zambanini et al., 2022) 90 minutes, 4 hours, 24 hours and 3 days after the onset of the stimulation. This approach allowed us to establish that β-catenin repositions to different genomic loci along stimulation time, showing that a definition of Wnt target genes must take into account the time-dimension. Moreover, β-catenin physical targets are largely cell-type specific, as only a subset of them is present across the examined contexts.
2022-09-30 | E-MTAB-12077 | biostudies-arrayexpress
Project description:Aortic valve stenosis (AVS) is a prevailing and life-threatening cardiovascular disease in adults over 75 years of age. However, the molecular mechanisms governing the pathogenesis of AVS are yet to be fully unraveled. With accumulating evidence that Wnt signaling plays a key role in the development of AVS, the involvement of intracellular Wnt molecules has become an integral study target in AVS pathogenesis. Thus, we hypothesized that the Wnt/β‐catenin pathway Wnt intracellular mediators, SFRP2, DVL2, GSK3β and β‐catenin are dysregulated in patients with AVS. Using immunohistochemistry, Real‐Time qPCR and Western blotting, we investigated the presence of SFRP2, GSK‐3β, DVL2 and β‐catenin in normal and stenotic human aortic valves. Markedly higher mRNA and protein expression of GSK‐3β, DVL2, β‐catenin and SFRP2 were found in stenotic aortic valves. This was further corroborated by observation of their abundant immunostaining, which displayed strong immunoreactivity in diseased aortic valves. Proteomic analyses of selective GSK3b inhibition in calcifying human aortic valve interstitial cells (HAVICs) revealed enrichment of proteins involved organophosphate metabolism, while reducing the activation of pathogenic biomolecular processes. Lastly, use of the potent calcification inhibitor, Fetuin A, in calcifying HAVICs significantly reduced the expression of Wnt signaling genes Wnt3a, Wnt5a, Wnt5b and Wnt11. The current findings of altered expression of canonical Wnt signaling in AVS suggest a possible role for regulatory Wnts in AVS. Hence, future studies focused on targeting these molecules are warranted to underline their role in the pathogenesis of the disease.
2021-09-09 | PXD020783 | Pride